Anticonvulsant Medications

Following an ABI, seizures can occur rather quickly due to the increased metabolic demands on the brain, increased ICP and the excessive amounts of neurotransmitters released. Seizures can occur within hours of the initial head trauma (immediate seizures), within the first week of sustaining an injury (early seizures), or within several months post injury (late seizures; Pagni & Zenga 2005; Temkin et al. 1995). These seizures can further complicate the injury as they can lead to increased damage (Schierhout & Roberts 2001). It has also been noted that the risk for developing or having late seizures post ABI is related to the severity of injury; those with a severe ABI are at greater risk (Ferguson et al. 2010; Temkin et al. 1995). For a more detailed discussion on seizures post ABI refer to Module 10.

Medications used to treat seizures post injury include carbamazepine (Tegretol), phenytoin (Dilantin), phenobarbital, primadone (Mysoline) and valporic acid (Depekane)/divalproex (Epival). These treatments have been used with both the adult and paediatric populations and have shown some success. Anticonvulsants have also shown some success in controlling or reducing the incidences of aggressive and agitated behaviours post ABI. For a more detailed discussion on the effects of anticonvulsants on aggression and agitation please refer to Module 8.

Carbamazepine

Carbamazepine has been proposed as an effective substitute for lithium in treating agitation and aggression following severe TBI. It has also been suggested as an alternative to anticonvulsants for controlling seizures without having harmful cognitive and behavioural side effects (Azouvi et al. 1999).

Table: Effects of Carbamazepine in the Treatment of Seizures and Aggression

Discussion

Azouvi et al. (1999) in an 8-week open drug trial administered carbamazepine (Tegretol) to 10 individuals with severe brain injury affected by significant behavioural challenges. According to the findings, patients showed improvements on a series of behavioural scales at the first assessment (two weeks post treatment), which were maintained only for the scales of irritability and disinhibition by the end of the trial. No significant changes on Mini Mental Status Exam (MMSE) were observed from baseline to any point of assessment. It should be mentioned as well that drowsiness was a frequently reported adverse event that limited the dosage from being increased in 40% of the participants, adding to the possibility that the apparent lack of sustained improvements in behaviour may be attributable to inadequate carbamazepine dosage.

Conclusions

There is Level 4 evidence that carbamazepine has no effect on cognitive performance post TBI.

There is Level 4 evidence that carbamazepine may decrease the incidence of aggressive behaviours following a TBI.

 

Carbamazepine has no effect on cognitive performance.

Carbamazepine helps in the reduction of aggression following brain injury.

 

Midazolam

Midazolam has been shown to be effective in controlling seizures post ABI. 

Table: Effects of Midazolam in the Treatment of Seizures

Discussion

There appears to be very little research evaluating the efficacy of anticonvulsants given to treat seizures following onset. We identified only one such study in this review. Wroblewski and Joseph (1992) reported on a collection of 10 case studies of patients with TBI treated with intramuscular (IM) midazolam for acute seizure cessation after other benzodiazepine drugs had failed. The authors reported that in all patients, seizures ceased within minutes of midazolam administration, with slight to moderate sedation being the only reported side effects. Future research is needed in this area.

Conclusion

There is Level 4 evidence that intramuscular midazolam can be used for acute seizure cessation. 

 

Intramuscular midazolam may be effective for acute seizure cessation.

 

Phenytoin

Early prevention of seizures has been attempted through administration of various anticonvulsants. It has been suggested that immediate administration of anticonvulsants, among them phenytoin, may be critical in reducing the risk of PTS developing (Pagni & Zenga 2005).

Table: Effects of Phenytoin in the Treatment of Seizures

Discussion

When it comes to seizure prophylaxis, phenytoin is the most commonly studied medication. When the administration of phenytoin is compared to a placebo, its effect on occurrence of early seizures is inconclusive; Temkin et al. (1990) and Bhullar et al. (2014) found it to be effective but Young et al. (1983a) did not. However, Phenytoin was found to be no more effective than placebo in preventing late seizures (McQueen et al. 1983; Temkin et al. 1990; Watson et al. 2004; Young et al. 1983b). In fact, Formisano et al. (2007) found that the occurrence of late seizures was significantly higher in patients treated with anti-epileptic medications than those who weren’t. It should be noted that Phenytoin has been shown to have a negative impact on recovery. Dikmen et al. (1991) found that severely injured individuals receiving phenytoin performed more poorly on neuropsychological measures than controls at one month but no significant differences were found at one year. The following year (12 to 24 months), phenytoin was shown to have a small but negative effect on cognition (Dikmen et al. 1991). Further, those taking phenytoin were shown to have longer hospital stays and worse functional outcomes at discharge than individuals receiving no treatment (Bhullar et al. 2014). Overall, there is not favourable evidence for the use of phenytoin for prevention of seizures.

When Phenytoin was compared to Levetiracetam, the two drugs were comparable in terms of seizure rates (Inaba et al. 2013; Jones et al. 2008; Kruer et al. 2013), complications, adverse drug reactions, mortality rates (Inaba et al. 2013) and length of hospital stay (Kruer et al. 2013). An RCT by Szaflarski et al. (2014) found similar results in terms of there being no difference for early seizure rates, death or adverse events between the two drugs; however, the authors found that those on Levetiracetam performed significantly better on the Disability Rating Scale at 3 and 6months (p=0.042), and the Glasgow Outcome Scale at 6 months (p=0.039) post intervention compared to the Phenytoin group. A meta-analysis by Zafar et al. (2012) also concluded that there was no superiority of either drug at preventing early seizures.

Conclusions

There is Level 1b evidence to suggest levetiracetam is as safe and effective as phenytoin in treatment and prevention of seizures in individuals in the intensive care unit post ABI.

There is Level 1b evidence that anticonvulsants given during the first 24 hours post ABI reduce the occurrence of early seizures (within the first week post injury).

There is Level 1a evidence that anticonvulsants given shortly after the onset of injury do not reduce mortality or persistent vegetative state or the occurrence of late seizures (past the first week post injury).

There is Level 1a evidence that seizure prophylactic treatment with phenytoin or valproate results in similar incidences of early or late seizures and similar mortality rates. 

 

Levetiracetam is as effective as phenytoin in treating and preventing seizures in individuals in the intensive care unit post ABI.

Anticonvulsants provided immediately post ABI reduce the occurrence of seizures only within the first week.

Anticonvulsants provided shortly post ABI do not reduce late seizures.

Anticonvulsants have negative consequences on motor tasks.

 

Phenobarbital

Phenobarbital, a barbiturate, has been used to control seizures post ABI. It has also been used as a sedative to relieve anxiety.

Table: Effects of Phenobarbital in the Treatment of Seizures

Discussion

Manaka (1992) conducted an RCT examining the effects of phenobarbital for seizure control on those who had sustained a severe TBI. Those in the treatment group were administered phenobarbital at the end of the first month of study. Individuals receiving phenobarbital were given 10 to 25 ug/mL for a two year period, at which time individuals were tapered off the medication. All subjects in the study were monitored for the next five years. Study results indicate that phenobarbital did not have a prophylactic effect on post-traumatic epilepsy.

Conclusion

There is Level 2 evidence indicating that phenobarbital given post ABI does not reduce the risk of late seizures.

 

Phenobarbital has not been shown to be effective in reducing the risk of late seizure development post ABI.

 

Valporic Acid/Divalproex

Valproic acid, an antiepileptic, has been used to successfully treat seizure disorders in both adults and children. Moreover, it has been used to treat bipolar, post-traumatic stress disorder (PTSD) and mania (McElroy et al. 1987). It has also been found to reduce episodic explosiveness with an individual with traumatic brain injury (TBI; Geracioti Jr 1994). Divalproex, another anticonvulsant, is believed to help reduce aggressive behaviours in individuals post TBI. 

Table: Effects of Valporic Acid and Divalproex on Reducing Aggressive Behaviour

Discussion

Wroblewski and colleagues (1997) examined the effects of valproic acid (Depakene) on reducing aggressive behaviour in a case series (n=5). Although the study reports that all patients showed a substantial reduction in challenging behaviour (i.e. outbursts, agitation, anger), no statistical analyses were performed. Researchers relied on visual inspection of data, and also presented graphs for only 3 of the 5 participants, rendering the interpretation of the findings difficult and potentially misleading. Further, patients were also part of a specialized neurobehavioural unit, which may have positively influenced the results.

Divalproex was used to treat symptoms of agitation in 29 patients with brain injuries (Chatham Showalter & Kimmel 2000). Symptoms decreased in the majority of patients, indicating that divalproex may be an effective treatment to reduce agitation following brain injury.

Conclusions

There is Level 4 evidence that valproic acid decreases the incidence of aggressive behaviours.

There is Level 4 evidence that divalproex decreases the incidence of agitation post TBI.

 

Valproic acid and divalproex may be used to decrease the incidence of aggressive behaviour; however, more research is needed.

 

Lamotrigine

The benefits of lamotrigine as an antiepileptic and mood stabilizer have been well established; however, its effectiveness as a mood stabilizer for patients with ABI has yet to be established (Gao & Calabrese 2005; Tidwell & Swims 2003).

Table: Effects of Lamotrigine on Reducing Aggressive Behaviour

Discussion

Results from a single study indicate that lamotrigine helps to reduce unwanted behaviours such as pathologic laughter but is not effective in reducing impulsivity (Chahine & Chemali 2006). All four participants were on other medications to control for additional behaviours, however in each case these medications were eventually eliminated once lamotrigine was introduced. No formal outcome assessments were conducted making it challenging to draw conclusions from this study. Further research is needed.

Conclusion

There is limited Level 4 evidence to suggest that lamotrigine helps to reduce inappropriate behaviours post TBI. More research is needed, with a greater number of subjects, to validate these findings.

 

Lamotrigine may be successful in reducing pathologic laughing post TBI.